Cancer has been postulated to be a disorder of differentiation. It is proposed to examine the ability of differentiation inducers to act as anti-tumor agents in solid tumors of epithelia, using a mouse epidermal cell model. Mouse epidermal cells exhibit 4 stages of differentiation similar to human epidermal cells, with characterized morphologic and immunologic markers, and they contain keratin, a protein marker common to internal lining epithelia such as nasopharynx, trachea, bladder and colon. Mouse epidermal cell clones recently developed in our laboratory offer an approach to these studies because they respond, like normal primary epidermal cultures, to extracellular Ca++ as a differentiation signal. Unlike primary cultures however, this model provides "normal", carcinogen-altered but non-tumorigenic, and benign and malignant tumor lines from a common cell lineage, suitable for reproducible tests of drug efficacy and mechanism of action. This model offers the additional advantages of permitting colony assays for more precise quantitation of drug effects as well as permitting selective quantitation of malignant vs. normal cells after drug treatment in mixed culture. Differentiation inducers active in vitro, like Ca++, or which may be active in vivo, like retinoids, Ca++ or K+ channel blockers, or modulators of protein kinase C, an enzyme involved in epidermal growth regulation, will be tested for ability to selectively attack neoplastic cells, either alone, or in combination with certain agents currently used in the treatment of human squamous cell cancers. The following alternative hypotheses are to be tested: First, that differentiation inducers act directly on tumor cells to arrest their growth and divert them toward terminal differentiation, or secondly, that they may be used to selectively protect normal cells, by temporary cell cycle arrest, from subsequent treatment with an anti-proliferative agent, which would be effective on the regulator-insensitive, proliferating tumor cells. The potency of each agent for inducing differentiation markers in normal vs. tumor cells and selectively inhibiting the growth of neoplastic cells will be assessed. Agents or combinations found to be effective in vitro will be tested in vivo. The proposed studies of these natural tissue specific agents in chemotherapy may suggest new, less toxic approaches to the treatment of human cancer.